PhD Scientific Days 2023

Budapest, 22-23 June 2023

Pharmaceutical Sciences II.

A Novel, Straightforward Synthetic Approach for the Preparation of Quinoline Photocages

Bence Kontra 1,2, Zoltán Mucsi 2,3,4, Petra Dunkel 1
1 Semmelweis University, Department of Organic Chemistry, Budapest
2 BrainVisionCenter, Department of Biological Chemistry, Budapest
3 Femtonics Ltd., Department of Chemistry, Budapest
4 University of Miskolc, Institute of Chemistry, Miskolc

Text of the abstract

Introduction: Photoremovable protecting groups (PPGs) allow the temporally and spatially selective release of biologically active agents, exploiting a light stimulus for the cleavage of a covalent bond between the protecting group and the attached substrate (1). Besides the general neuroscientific applications, they can serve as a drug-delivery system for different small molecule drugs (2). Quinoline-derived PPGs were first described by Dore et. al. (3). Importantly, these readily modifiable structures can be used efficiently for two-photon photolysis.
Aims: On the one hand, we have set out to develop a new shorter, scalable synthesis which can be utilized for the easy preparation of efficient probes. On the other hand, we aimed to prepare and characterize novel quinoline PPGs inspired by the 8-dimethylaminoquinoline caging chromophore.
Method: The novel derivatives were prepared by a four-step synthesis. The selenium dioxide oxidation step proved to be challenging, therefore other alternatives were tested. As model substrate, acetic acid was used via an ester linkage. The probes were characterized by their UV/VIS absorption and photolysis. Moreover, to study the mechanism of the photolysis, density functional theory calculations were performed.
Results: A robust synthetic pathway for aminoquinoline photocages was developed. The novel PPGs exhibited high photolysis efficiency and low fluorescence, comparable to literature reference compounds, demonstrating the utility of these probes for uncaging and drug delivery applications.
Conclusion: Using a short synthesis, numerous novel aminoquinoline photocages were prepared. Alternative approaches were tested for more sensitive substrates. Based on the results of the spectroscopic and photolysis studies, we plan to use the most efficient probes for preparing the caged version of neurotransmitters for biological studies.
Funding: The research was funded by the National Research, Development and Innovation Office (NKFIH), grant no. SNN 135825 and by the ÚNKP-22-3 New National Excellence Program of the Ministry of Innovation and Technology. Z.M. is recipient of the János Bolyai Research Scholarship of the Hungarian Academy of Sciences.
1) Chem. Rev. 2013, 113, 119–191
2) J. Control. Release 2019, 298, 154-176
3) Org. Lett. 2002, 4, 3419-3422
Semmelweis University, Doctoral School of Pharmaceutical Sciences
Supervisor: Dr. Dunkel Petra